The present invention relates to a novel macrolide compound or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, to a composition comprising the compound and a suitable carrier, a method of preparing the compound, and a method of treatment and prevention of infections in a mammal.
Erythromycins A, B, C and D, represented by formula (I), 
are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterial agents, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
U.S. Pat. No. 5,444,051 and U.S. Pat. No. 5,770,579 disclose 6-O-substituted-3-oxoerythromycin derivatives in which the substituents are selected from alkyl, xe2x80x94CONH2, xe2x80x94CONHC(O)alkyl and xe2x80x94CONHSO2alkyl. PCT application WO 97/10251, published Mar. 20, 1997, discloses 6-O-methyl 3-descladinose erythromycin derivatives.
European Patent Application 0216169, published Apr. 1, 1987, discloses erythromycin A 6-carbamate derivatives.
European Patent Application 596802, published May 11, 1994, discloses bicyclic 6-O-methyl-3-oxoerythromycin A derivatives.
PCT application WO 92/09614, published Jun. 11, 1992, discloses tricyclic 6-O-methylerythromycin A derivatives.
In one aspect, the invention relates to a compound represented by a formula selected from the group consisting of:
a compound of the formula 
a compound of the formula 
a compound of the formula 
a compound of the formula 
a compound of the formula 
a compound of the formula 
a compound of the formula 
a compound of the formula 
a compound of the formula 
or a pharmaceutically acceptable salt, solvate, ester, or prodrugs thereof, wherein:
Rp is hydrogen or a hydroxy protecting group;
A is xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94;
M is either absent or selected from the group consisting of:
(a) xe2x80x94(CH2)lxe2x80x94 where l is 1 to 5,
(b) xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94 where m is 0 to 3,
(c) xe2x80x94(CH2)nxe2x80x94Cxe2x89xa1Cxe2x80x94 where n is 0 to 3;
R1 is selected from the group consisting of:
(a) hydrogen,
(b) aryl,
(c) substituted aryl,
(d) heteroaryl,
(e) substituted heteroaryl, and
(f) Ar1xe2x80x94Ar2 wherein Ar1 and Ar2 are independently selected from the group consisting of:
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl, and
(iv) substituted heteroaryl;
R is selected from the group consisting of:
(a) aryl,
(b) substituted aryl,
(c) heteroaryl,
(d) substituted heteroaryl, and
(e) Ar1xe2x80x94Ar2 wherein Ar1 and Ar2 are independently selected from the group consisting of:
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl, and
(iv) substituted heteroaryl;
X is selected from the group consisting of:
(a) O
(b) Nxe2x80x94OH
(c) Nxe2x80x94Oxe2x80x94Uxe2x80x94R3 wherein U is selected from the group consisting of:
(i) xe2x80x94C(O)xe2x80x94
(ii) xe2x80x94C1-C6 alkyl,
(iii) xe2x80x94C1-C6 alkenyl, and
(iv) xe2x80x94C1-C6 alkynyl,
and R3 is selected from the group consisting of:
(i) hydrogen,
(ii) aryl,
(iii) substituted aryl,
(iv) heteroaryl,
(v) substituted heteroaryl, and
(vi) Ar1xe2x80x94Ar2 wherein Ar1 and Ar2 are independently selected from the group consisting of:
(1) aryl,
(2) substituted aryl,
(3) heteroaryl, and
(4) substituted heteroaryl;
W is selected from the group consisting of
(a) xe2x80x94NHxe2x80x94(CH2)pxe2x80x94 wherein p is 0 to 5,
(b) xe2x80x94(CH2)qxe2x80x94 wherein q is 0 to 5,
(c) xe2x80x94Oxe2x80x94(CH2)rxe2x80x94 wherein r is 0 to 5,
(d) xe2x80x94NHxe2x80x94C1-C6 alkenyl-,
(e) xe2x80x94C1-C6 alkenyl-,
(f) xe2x80x94Oxe2x80x94C1-C6 alkenyl-,
(g) xe2x80x94NH-C1-C6 alkynyl-,
(h) xe2x80x94C1-C6 alkynyl-, and
(i) xe2x80x94O-C1-C6 alkynyl-,
R4 is selected from the group consisting of:
(a) hydrogen,
(b) aryl,
(c) substituted aryl,
(d) heteroaryl,
(e) substituted heteroaryl, and
(f) Ar1xe2x80x94Ar2 wherein Ar1 and Ar2 are independently selected from the group consisting of:
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl, and
(iv) substituted heteroaryl; and
Ra, Rb, Rc and Rd are independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6 alkyl, optionally substituted with one or more substituents selected from the group consisting of:
(i) xe2x80x94Lxe2x80x94Mxe2x80x94R1 or xe2x80x94Lxe2x80x94Mxe2x80x94R2, wherein M, R1, and R2 are as defined above, and L is either absent or selected from the group consisting of:
(1) xe2x80x94C(O)NHxe2x80x94;
(2) xe2x80x94NHC(O)xe2x80x94;
(3) xe2x80x94NHxe2x80x94;
(4) xe2x80x94N(CH3)xe2x80x94;
(5) xe2x80x94Oxe2x80x94;
(6) xe2x80x94S(O)xxe2x80x94, wherein x is 0, 1, or 2;
(7) xe2x80x94C(xe2x95x90NH)NHxe2x80x94;
(8) xe2x80x94C(O)Oxe2x80x94;
(9) xe2x80x94OC(O)xe2x80x94;
(10) xe2x80x94OC(O)NHxe2x80x94;
(11) xe2x80x94NHC(O)Oxe2x80x94; and
(12) xe2x80x94NHC(O)NHxe2x80x94; and
(ii) halogen;
(c) C3-C7 cycloalkyl;
(d) heterocycloalkyl; and
(e) substituted heterocycloalkyl;
or any one pair of substituents selected from the group consisting of RaRb, RaRc, RaRd, RbRc, RbRd or RcRd taken together with the atom or atoms to which they are attached form a 3- to 7- membered ring optionally containing a hetero function selected from the group consisting of xe2x80x94Oxe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94N(C1-C6 alkyl-)xe2x80x94; xe2x80x94N(aryl-C1-C6 alkyl-)xe2x80x94; xe2x80x94N(substituted aryl-C1-C6 alkyl-)xe2x80x94; xe2x80x94N(heteroaryl-C1-C6 alkyl-)xe2x80x94; xe2x80x94N(substituted heteroaryl-C1-C6 alkyl-)xe2x80x94; xe2x80x94S(O)xxe2x80x94, wherein x is 0, 1, or 2; xe2x80x94C(O)xe2x80x94NHxe2x80x94; xe2x80x94NHxe2x80x94C(O)xe2x80x94; xe2x80x94C(O)xe2x80x94NR12xe2x80x94; and xe2x80x94NR12xe2x80x94C(O)xe2x80x94; wherein R12 is hydrogen, C1-C3 alkyl, C1-C3 alkyl substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
In another aspect, the invention relates to a process for preparing a compound of formula I, II, II-A, III, IV, IV-A, V, VI, and VI-A, as defined above, comprising the steps of:
(a) reacting a compound having a formula: 
xe2x80x83wherein V is selected from the group consisting of:
(i) O,
(ii) Nxe2x80x94Oxe2x80x94(CH2)sxe2x80x94Rx, wherein s is 0 to 5 and Rx is selected from the group consisting of:
(1) hydrogen,
(2) alkyl,
(3) substituted alkyl,
(4) aryl,
(5) substituted aryl,
(6) heteroaryl, and
(7) substituted heteroaryl,
(iii) Nxe2x80x94Oxe2x80x94C(O)xe2x80x94(CH2)sxe2x80x94Rx, wherein s and Rx is as defined above,
(iv) Nxe2x80x94Oxe2x80x94C(Ry)(Rz)xe2x80x94Oxe2x80x94Rx, wherein Rx is as defined above, and Ry and Rz are independently selected from the group consisting of:
(1) hydrogen,
(2) unsubstituted C1-C12-alkyl,
(3) C1-C12-alkyl substituted with aryl, and
(4) C1-C12-alkyl substituted with substituted aryl,
or Ry and Rz taken together with the carbon to which each is attached form a C3-C12-cycloalkyl ring; and Rp and Rp2 are as defined above;
with either (i) an isocyanate reagent of the formula Oxe2x95x90Cxe2x95x90Nxe2x80x94Mxe2x80x94R1, Oxe2x95x90Cxe2x95x90Nxe2x80x94Mxe2x80x94R2, Oxe2x95x90Cxe2x95x90Nxe2x80x94C(O)xe2x80x94Mxe2x80x94R1, Oxe2x95x90Cxe2x95x90Nxe2x80x94C(O)xe2x80x94Mxe2x80x94R2, Oxe2x95x90Cxe2x95x90Nxe2x80x94S(O)2xe2x80x94Mxe2x80x94R1, or Oxe2x95x90Cxe2x95x90Nxe2x80x94S(O)2xe2x80x94Mxe2x80x94R2, wherein M, R1, and R2 are as defined above, or (ii) an activated isocyanate derivative followed by an alkylation with a compound of the formula X1xe2x80x94Mxe2x80x94R1 or X1xe2x80x94Mxe2x80x94R2, wherein M, R1, and R2 are as defined above, and X1 is a halide or a leaving group, and optionally removing the activating group;
(b) carrying out one or more of the following steps in any suitable order:
(i) removing any hydroxy protecting group that may be present;
(ii) removing a protecting group on the C9-oxime;
(iii) converting the C9-oxime into a keto moiety;
(iv) removing the cladinose sugar and oxidizing the resulting hydroxy group;
(v) converting the 11,12-diol into an 11,12-carbonate;
(vi) converting the 11,12-diol into an 11,12-carbamate optionally substituted on the nitrogen atom; and
(vi) preparing a tricyclic imine derivative from the 11,12-carbamate.
In a preferred process, the 11,12-carbonate is prepared by treating the compound of the formula: 
wherein R is selected from the group consisting of xe2x80x94Mxe2x80x94R1, xe2x80x94Mxe2x80x94R2, xe2x80x94C(O)xe2x80x94Mxe2x80x94R1, xe2x80x94C(O)xe2x80x94Mxe2x80x94R2, xe2x80x94S(O)2xe2x80x94Mxe2x80x94R1, xe2x80x94S(O)2xe2x80x94Mxe2x80x94R2, with carbonyldiimidazole and sodium hexamethyldisilazide and optionally removing the 2xe2x80x2-hydroxy group.
In another preferred process, the 11,12-carbamate optionally substituted on the nitrogen atom is prepared by the steps of:
(a) treating the compound of the formula: 
wherein R is selected from the group consisting of xe2x80x94Mxe2x80x94R1, xe2x80x94Mxe2x80x94R2, xe2x80x94C(O)xe2x80x94Mxe2x80x94R1, xe2x80x94C(O)xe2x80x94Mxe2x80x94R2, xe2x80x94S(O)2xe2x80x94Mxe2x80x94R1, xe2x80x94S(O)2xe2x80x94Mxe2x80x94R2, optionally with a reagent combination selected from the group consisting of:
(1) an alkali metal hydride and a phosgene reagent selected from phosgene, diphosgene and triphosgene under anhydrous conditions, followed by a base catalyzed decarboxylation, and
(2) reaction with methanesulfonic anhydride in pyridine, followed by treatment with an amine base,
(b) treating the compound of formula (i) or (ii) or the compound obtained in step (a) with an alkali metal hydride base and carbonyldiimidazole;
(c) reacting the compound obtained in step (b) with an amine of the formula H2Nxe2x80x94Wxe2x80x94R4, wherein W and R4 are as defined above, anhydrous ammonia, or ammonium hydroxide;
(d) optionally removing the cladinose sugar and oxidizing the resulting hydroxy group; and
(e) optionally removing any hydroxy protecting group that may be present.
In another preferred process, the tricyclic imine is prepared by the steps of:
(a) treating a compound of the formula: 
wherein R is as defined above, with a diamine of the formula: 
wherein Ra, Rb, Rc and Rd, are as previously defined;
(b) cyclizing the compound obtained in step (a);
(c) optionally removing the cladinose sugar and oxidizing the resulting hydroxy group; and
(d) optionally removing any hydroxy protecting group that may be present.
In yet another aspect, the invention relates to a pharmaceutical composition comprising a compound as described above and a pharmaceutically acceptable carrier.
Yet another aspect of the invention relates to a method of treating a bacterial infection comprising administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment.
The terms xe2x80x9cC1-C6 alkylxe2x80x9d as used herein refer to saturated, straight, or branched chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and six carbon atoms by removal of a single hydrogen atom. In general, a group denoted as Cx-Cy, wherein x and y are integers, refers to a group of x to y carbon atoms. For example, the group Cx-Cy alkyl, wherein x is 1 and y is 3, includes C1-C3 alkyl radicals such as methyl, ethyl, propyl, and isopropyl. Exemplary C1-C6alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl. Examples of C1-C12 alkyl radicals include all the foregoing examples, as well as n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-docecyl.
The term xe2x80x9cC1-C6 alkenylxe2x80x9d as used herein refers to straight- or branched-chain hydrocarbon radicals comprising one to six carbon atoms, respectively, which contain one or more carbon-carbon double bonds. Compounds of the invention have either a known configuration or exist as a mixture of isomers.
The term xe2x80x9cC1-C6 alkynylxe2x80x9d used herein refers to straight- or branched-chain hydrocarbon radicals comprising one to six carbon atoms, respectively, which contain one or more carbon-carbon triple bonds. Compounds of the invention have either a known configuration or exist as a mixture of isomers.
The term xe2x80x9carylxe2x80x9d as used herein refers to a mono-, fused bicyclic or fused tricyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, anthracenyl, phenanthrenyl, biphenylenyl, fluorenyl, and the like.
The term xe2x80x9csubstituted arylxe2x80x9d as used herein refers to an aryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3 alkyl, C1-C6 alkoxy, C1-C6 alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substitutent may be an aryl, heteroaryl, or heterocycloalkyl group. Substituents also include alkenyloxy, for example, methylenedioxy and ethylenedioxy. The substituted aryl groups also include tetrafluorophenyl and pentafluorophenyl.
The terms xe2x80x9chaloxe2x80x9d, xe2x80x9chalidexe2x80x9d, and xe2x80x9chalogenxe2x80x9d as used herein refer to an atom selected from fluorine, chlorine, bromine, and iodine.
The term xe2x80x9cheteroarylxe2x80x9d as used herein refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; one, two, or three ring atoms may be additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
The term xe2x80x9cheterocyclicxe2x80x9d, xe2x80x9cheterocyclexe2x80x9d, and xe2x80x9cheterocycloalkylxe2x80x9d as used herein refers to a non-aromatic partially unsaturated or fully saturated 3- to 10-membered ring system which includes single rings of 3 to 8 atoms in size and bi- or tri-cyclic ring systems which may include aromatic six-membered aryl or heteroaryl rings fused to a non-aromatic ring. These heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
Representative heterocycles include pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
The term xe2x80x9csubstituted heteroarylxe2x80x9d as used herein refers to a heteroaryl group as defined above substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, cyano, C1-C3 alkyl, C1-C6 alkoxy, C1-C6 alkoxy substituted with aryl, haloalkyl, thioalkoxy, alkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, mercapto, xe2x80x94SO3H, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substitutent may be an aryl, arylalkyl, cycloalkyl, heteroaryl, or heterocycloalkyl group.
The term xe2x80x9csubstituted heterocycloalkylxe2x80x9d as used herein, refers to a heterocycloalkyl group, as defined above, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, cyano, C1-C3 alkyl, C1-C6 alkoxy, C1-C6 alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substitutent may be an aryl, heteroaryl, or heterocycloalkyl group.
The term xe2x80x9chydrocarbylxe2x80x9d as used herein refers to an alkyl, alkenyl, or alkynyl group as described above. Preferably, hydrocarbyl groups have from one to six carbon atoms as defined for C1-C6 alkyl, C1-C6 alkenyl, and C1-C6 alkynyl groups as described above.
The term xe2x80x9chydroxy-protecting groupxe2x80x9d as used herein refers to an easily removable group to which are known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, c.f., for example T. H. Wiley and Sons, New York (1991). Examplary hydroxy-protecting groups are methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, acyl substituted with an aromatic group, and the like.
The term xe2x80x9cprotected hydroxyxe2x80x9d as used herein refers to a hydroxy group protected with a hydroxy protecting group as defined above including, but not limited to, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl, and the like.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein refers to those carboxylate salts, esters, and prodrugs of the compound of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. Pharmaceutically acceptable salts are well known in the art and refer to the relatively non-toxic, inorganic and organic acid addition salts of the compound of the present invention. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977) which is incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
As used herein, the term xe2x80x9cpharmaceutically acceptable esterxe2x80x9d refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term xe2x80x9cpharmaceutically acceptable solvatexe2x80x9d represents an aggregate that comprises one or more molecules of the solute, such as a compound of the invention, with one or more molecules of solvent.
The term xe2x80x9cpharmaceutically acceptable prodrugsxe2x80x9d as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Numerous asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof.
A preferred compound of the invention is represented by a formula: 
wherein R1 is as previously defined.
Another preferred compound of the invention is represented by a formula: 
wherein R1 is as previously defined.
An additional preferred compound of the invention is represented by a formula: 
wherein R1 is as previously defined.
Yet another preferred compound is represented by a formula: 
wherein R1 is as previously defined.
Still another preferred compound is represented by a formula: 
wherein R4 is as previously defined and p is 0 to 5.
Still another additional compound is represented by a formula: 
wherein R4 is as previously defined and p is 0 to 5.
Representative compounds of the invention include, but are not limited to the following.
Compound of formula (IV-A): wherein A is xe2x80x94Oxe2x80x94; X is Nxe2x80x94OH; xe2x80x94Mxe2x80x94 is absent; R2 is phenyl; and Rp is hydrogen;
Compound of formula (II-A): wherein A is xe2x80x94Oxe2x80x94; X is Nxe2x80x94OH; xe2x80x94Mxe2x80x94 is absent; R2 is hydrogen; and Rp is hydrogen;
Compound of formula (II-A): wherein A is xe2x80x94Oxe2x80x94; X is Nxe2x80x94OH; xe2x80x94Mxe2x80x94 is xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94; R2 is 3-quinolyl; and Rp is hydrogen;
Compound of formula (II): wherein W is absent, R4 is H; X is O; xe2x80x94Mxe2x80x94 is xe2x80x94CH2-CHxe2x95x90CHxe2x80x94 R1 is hydrogen; and Rp is hydrogen; and
Compound of formula (II-A): wherein A is xe2x80x94NHxe2x80x94; X is O; xe2x80x94Mxe2x80x94 is -CH2xe2x80x94CHxe2x95x90CHxe2x80x94; R2 is 3-quinolyl; and Rp is hydrogen.
The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer""s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eyd ns are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
According to the methods of treatment of the present invention, bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. By a xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
The total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more, such as from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 2000 mg of a compounds of the invention per day in a single or multiple doses.
Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: AIBN for azobisisobutyronitrile; Bu3SnH for tributyltin hydride; CDI for carbonyldiimidazole; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DEAD for diethylazodi-carboxylate; DMF for dimethylformamide; DMSO for dimethylsulfoxide; DPPA for diphenylphosphoryl azide; Et3N for triethylamine; EtOAc for ethyl acetate; Et2O for diethyl ether; EtOH for ethanol; HOAc for acetic acid; MeOH for methanol; NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NCS for N-chlorosuccinimide; NMMO for N-methylmorpholine N-oxide; Me2S for dimethyl sulfide; TEA for triethylamine; THF for tetrahydrofuran; and TPP for triphenylphosphine. Starting materials, reagents, and solvents are available from Aldrich Chemical Company (Milwaukee, Wis.) unless otherwise noted herein.
The compounds and processes of the present invention will be better understood in connection with the following synthetic Schemes, which illustrate the methods by which the compounds of the invention may be prepared. The compounds of formulae I, II, II-A, III, IV, IV-A, V, VI, and VI-A may be prepared by a variety of synthetic routes. Representative procedures are shown below in Schemes 1-8. The groups A, M, X, W, R1, R2, R3, R4, Ra, Rb, Rc, Rd, Rp, and Rp2 are as previously defined unless otherwise noted. It will be readily apparent to one of ordinary skill other compounds of formulae I, II, II-A, III, IV, IV-A, V, VI, and VI-A can be synthesized by substitution of the appropriate reactants and agents in the syntheses shown below. It will also be apparent to one skilled in the art that the selective protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order, depending on the nature of the substrate compound and the groups A, M, X, W, R1, R2, R3, R4, Rp, and Rp2.
The conversion of erythromycin A (available from Abbott Laboratories, Abbott Park, Ill.) to 1 is described in U.S. Pat. Nos. 4,990,602; 4,331,803; 4,680,368; and 4,670,549; and European Patent Application EP 260,938, the disclosures of which are herein incorporated by reference. The C-9-carbonyl group of the erythromycin A is typically protected as an oxime 1, wherein V is Nxe2x80x94Oxe2x80x94(CH2)sxe2x80x94Rx, Nxe2x80x94Oxe2x80x94C(O)xe2x80x94(CH2)sxe2x80x94Rx, or Nxe2x80x94Oxe2x80x94C(Ry)(Rz)xe2x80x94Oxe2x80x94Rx, wherein s is 0 to 5 and Rx is (a) hydrogen, (b) alkyl, (c) substituted alkyl, (d) aryl, (e) substituted aryl,
(f) heteroaryl, and (g) substituted heteroaryl, and wherein Ry and Rz are independently selected from (a) hydrogen, (b) unsubstituted C1-C12-alkyl, (c) C1-C12-alkyl substituted with aryl, and
(d) C1-C12-alkyl substituted with substituted aryl, or Ry and Rz taken together with the carbon to which they are attached form a C3-C12-cycloalkyl ring. A preferred protected oxime group
V is Nxe2x80x94Oxe2x80x94(1-isopropoxycyclohexyl) or Nxe2x80x94Oxe2x80x94C(O)-phenyl (i.e. Nxe2x80x94Oxe2x80x94benzoyl).
The 2xe2x80x2- and 4xe2x80x3-hydroxy groups of the C-9 protected erythromycin A can be treated with a suitable hydroxy protecting reagent in an aprotic solvent. Hydroxy protecting reagents include, for example, acetic anhydride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, or a trialkylsilyl chloride in an aprotic solvent. Examples of aprotic solvents are dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone, dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. Aprotic solvents do not adversely affect the reaction, and are preferably dichloromethane, chloroform, DMF, tetrahydrofuran, N-methyl pyrrolidinone or a mixture thereof. The protection of the 2xe2x80x2- and optionally the 4xe2x80x3-hydroxy groups of the C-9 protected erythromycin A may be accomplished sequentially or simultaneously. The variables Rp and Rp2 denote a hydroxy protecting group when used throughout the specification in the structural formulas. Preferred protecting groups include, but are not limited to, acetyl, trimethylsilyl, and benzoyl. A thorough discussion of protecting groups and the solvents in which they are most effective is provided by T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Son, Inc., 1991.
General methods of introducing the carbamate to the macrolide proceed with various reagents and conditions. Representative syntheses for attaching the carbamate to the C6-hydroxy are illustrated below in Scheme 1. 
The introduction of the carbamate to the macrolide at 6-O-hydroxy can be accomplished by treating compound 1 with an isocyanate reagent in a polar or nonpolar aprotic solvent. Suitable isocyanate reagents include, but are not limited to, hydrocarbyl isocyanates, acyl isocyanates, and arylacyl isocyanates. For the sake of convenience, the isocyanate reagents are referred to by the general formula Oxe2x95x90Cxe2x95x90Nxe2x80x94R, wherein R is a hydrocarbyl, hydrocarbylcarbonyl, or a hydrocarbylsulphonyl. In a preferred reagent, R denotes a group of the formula xe2x80x94Mxe2x80x94R1,
xe2x80x94Mxe2x80x94R2, xe2x80x94C(O)xe2x80x94Mxe2x80x94R1, xe2x80x94C(O)xe2x80x94Mxe2x80x94R2, xe2x80x94SO2xe2x80x94Mxe2x80x94R1, xe2x80x94SO2xe2x80x94Mxe2x80x94R2, wherein M is an alkyl, alkenyl, or alkynyl group of the formulas xe2x80x94(CH2)lxe2x80x94, xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94, and xe2x80x94(CH2)nxe2x80x94Cxe2x89xa1Cxe2x80x94, respectively, wherein 1 is 0 to 5, m is 0 to 3, and n is 0 to 3; R1 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and a group Ar1xe2x80x94Ar2, wherein Ar1 and Ar2 are independently selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and R2 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, and Ar1xe2x80x94Ar2, wherein Ar1 and Ar2 are as previously defined. Representative reagents include, but are not limited to compounds of the formula Oxe2x95x90Cxe2x95x90Nxe2x80x94Mxe2x80x94R1, Oxe2x95x90Cxe2x95x90Nxe2x80x94Mxe2x80x94R2, Oxe2x95x90Cxe2x95x90Nxe2x80x94C(O)xe2x80x94Mxe2x80x94R1, Oxe2x95x90Cxe2x95x90Nxe2x80x94C(O)xe2x80x94Mxe2x80x94R2, Oxe2x95x90Cxe2x95x90Nxe2x80x94SO2xe2x80x94Mxe2x80x94R1, or Oxe2x95x90Cxe2x95x90Nxe2x80x94SO2xe2x80x94Mxe2x80x94R2, or an isocyanate of an acyl derivative. The reaction can be accomplished at 0xc2x0 C. and gradually warmed up to room temperature or can be heated to reflux from 1-48 hours. Exemplary aprotic solvents suitable for the reaction include, but are not limited to, tetrahydrofuran, dimethyl sulfoxide, toluene, dioxane, dimethyl formamide, methylene chloride, and the like, or combination of the above solvents, such as tetrahydrofuran and dimethyl sulfoxide. Additionally, CuCl (0.05 to 1 eq.) can be optionally added.
An exemplary method of introducing the carbamate to the C6-hydroxy involves using a hydrocarbyl, acyl, or arylacyl isocyanate reagent. To compound 1 in an aprotic solvent, such as THF, at xe2x88x9210xc2x0 C. to 40xc2x0 C. is added the isocyanate reagent, for example allyl isocyanate (1-4 eq.), wherein R is an allyl moiety. CuCl (0.05-1 eq.) is added to the mixture. The reaction mixture is stirred at room temperature to 40xc2x0 C. overnight. The reaction mixture was taken up in ethyl acetate and washed with NaHCO3 and brine to give the 6-O-carbamate derivative 2 wherein R is the group defined above.
According to another exemplary method, an activated isocyanate is introduced to the C6-position of the erythromycin 1 followed by alkylation with an appropriate electrophile. Reacting compound 1 with the activated isocyanate under reaction conditions similar to those previously described above can give a corresponding 6-O-carbamate 2a, from which the activating group can be optionally removed. The carbamate 2a, or its derivatives wherein the activating group is already removed, can be reacted with a compound of the formula R1xe2x80x94Mxe2x80x94X1, wherein R1 and M are as previously defined and X1 is a halide or a suitable leaving group, for example acetate, tosylate, or mesylate. Exemplary activated isocyanate reagents for the reaction include, but are not limited to acyl isocyanates, sulphonyl isocyanates, and the like. A preferred isocyanate for the reaction is trichloroacetyl isocyanate. Suitable bases include, but are not limited to, potassium t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, and the like, or a combination thereof. The reaction is carried out in an aprotic solvent, as described above, to introduce the group xe2x80x94Mxe2x80x94R1 to the attached carbamate represented by 3.
Substituting R2 for R1 in R1xe2x80x94Mxe2x80x94X1, in the above process provides the compound 3 wherein R1 is R2, and wherein R2 is as previously defined. 
Deprotection of the C9-oxime of compound 2 or 3, wherein V is a protected oxime, is accomplished under neutral, acidic or basic conditions. Exemplary conditions for deprotecting a protected oxime of the formula Nxe2x80x94Oxe2x80x94C(O)xe2x80x94(CH2)sxe2x80x94Rx include, but are not limited to, treatment with an alcoholic solvent at room temperature or at reflux. Preferably, the 9-oxime is deprotected in this manner when Rp is an ester, such as acetate or benzoate. Alcoholic solvents preferred for the deprotection are methanol or ethanol. Exemplary conditions for converting the protected oxime Nxe2x80x94Oxe2x80x94C(Ry)(Rz)xe2x80x94xe2x80x94Rx, wherein Rx, Ry, and Rz are as defined above, to the oxime (Nxe2x80x94OH) involve treating compound 2 or 3 with aqueous acid in acetonitrile. Aqueous acids suitable for the reaction include, but are not limited to, aqueous acetic acid, hydrochloric acid, and sulfuric acid. During the deprotection of the oxime, the 2xe2x80x2- and 4xe2x80x3-hydroxy protecting groups (Rp and Rp2) can be removed in process. A thorough discussion of the procedures, reagents and conditions for removing protecting groups is discussed by T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Son, Inc., (1991), which is herein incorporated by reference. 
As shown in Scheme 3, the deoximation reaction can be carried out by reacting the C-9 oxime, with an inorganic sulfur oxide or an inorganic nitrite salt in a protic solvent. Exemplary inorganic sulfur oxide compounds are sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate, potassium metabisulfite, and the like. Suitable inorganic nitrite salts include, for example, sodium nitrite or potassium nitrite, and the like. Examples of the solvents used are protic solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol, or a mixture of one or more of the mentioned solvents, and the like. The reaction is optionally carried out in the presence of an organic acid, such as formic acid, acetic acid and trifluoroacetic acid. Hydrochloric acid is also suitable for the reaction. The amount of acid used is from about 1 to about 10 equivalents of the amount of compound 4. In a preferred embodiment, the reaction of compound 4 is carried out using sodium nitrite and HCl in ethanol and water to give compound 5. 
The cladinose moiety of compound 2 or 5 is removed by mild aqueous acid hydrolysis to give 6. Representative acids include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid or trifluoroacetic acid. Suitable solvents for the reaction include methanol, ethanol, isopropanol, butanol and the like. Reaction times are typically 0.5 to 24 hours. The reaction temperature is preferably xe2x88x9210xc2x0 C. to 70xc2x0 C.
The 2xe2x80x2-hydroxy group of the macrolide is optionally protected as previously described using a hydroxy protecting reagent in an aprotic solvent. Preferred hydroxy protecting reagents are acetic anhydride, benzoyl anhydride, benzyl chloroformate or trialkylsilyl chloride. Preferably, the aprotic solvent is dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. A particularly preferred protecting group Rp is acetate or benzoate. Protection of the hydroxy group can be accomplished before or after the descladinozation reaction.
The 3-hydroxy group of 6 is oxidized to the ketone 7 using a modified Swem oxidation procedure or Corey-Kim oxidation conditions. Suitable oxidizing agents are N-chloro-succinimide-dimethyl sulfide or carbodiimide-dimethylsulfoxide. In a typical example, 6 is added into a pre-formed N-chlorosuccinimide and dimethyl sulfide complex in a chlorinated solvent, such as methylene chloride, at xe2x88x9210 to 25xc2x0 C. After stirring for 0.5-4 hours, a tertiary amine, such as triethylamine or Hunig""s base, is added to produce the corresponding ketone.
Compound 2 or 7 can be further treated to obtain 11,12-carbamate compounds of formula (II), (II-A), (IV), (IV-A), (IV), and (VI-A) and the tricyclic imine derivatives of formula (I), (III), and (V), as illustrated below in Schemes 5 and 6. In the case of compound 2, cleavage of the cladinose sugar and oxidation of the 3-hydroxy to a 3-keto group can be accomplished after 11,12-carbamate formation. 
According to Scheme 5, intermediate compound 8 may be prepared from compound 7, by treatment of the latter under anhydrous conditions with an alkali metal hydride or bis(trimethylsilyl) amide in the presence of carbonyldiimidazole in an aprotic solvent. The aprotic solvent can be selected from the group as previously defined. Exemplary reagents can be selected from sodium hydride, lithium hydride, sodium hexamethyldisilazide, and lithium hexamethyldisilazide. Preferably, the solvent is tetrahydrofuran, dimethylformamide, or a mixture thereof. The reaction may require cooling or heating, depending upon the conditions used. The reaction temperature may be from xe2x88x9220xc2x0 C. to 70xc2x0 C., and preferably from 0xc2x0 C. to room temperature. The reaction may require 0.5 hours to 10 days, and is preferably accomplished in 1 to 5 days.
Alternatively, compound 7 is treated with an alkali metal hydride and a phosgene reagent under anhydrous conditions, followed by a base catalyzed decarboxylation, or can be treated with methanesulfonic anhydride in pyridine, followed by treatment with an amine base to provide a suitable intermediate for treatment with the alkali metal hydride base and carbonyldiimidazole to give compound 8 in a stepwise manner. Preferably, the phosgene reagent is phosgene, diphosgene, or triphosgene.
Compound 8 is reacted with a primary amine R4xe2x80x94Wxe2x80x94NH2, wherein R4 and W are as previously defined. The reaction is carried out in a suitable solvent from room temperature to reflux temperature for about 4 to about 48 hours. Exemplary solvents are acetonitrile, tetrahydrofuran, dimethyl formamide, dimethylsulfoxide, dimethyl ether, N-methyl pyrrolidinone, water, or a mixture thereof. Preferred solvents are aqueous acetonitrile, and aqueous DMF.
The prepared 11,12-carbamate derivatives are optionally deprotected and a compound of formula (II), (IV), and (VI) can be isolated. When the protecting group Rp or Rp2 is an ester, the protecting group may be removed by treatment with an organic alcohol, such as methanol or ethanol. Exemplary esters which can be deprotected by treating the ketolide derivatives with an organic alcohol are acetate, benzoate, and the like. When the protecting group is a trialkylsilyl group, deprotection by treatment with fluoride in a polar organic solvent, such as THF or acetonitrile, or aqueous acid hydrolysis is preferred.
To obtain derivatives of formula (II-A), (IV-A), and (VI-A), wherein A in the structural formula corresponds to xe2x80x94NHxe2x80x94, compound 8 is reacted with aqueous ammonia hydroxide or anhydrous ammonia, preferably in acetonitrile, under the conditions as described above for the primary amine optionally followed by the deprotection of the 2xe2x80x2 hydroxy protecting group as described above. 
As illustrated above in Scheme 6, compound 8 can be reacted with a diamine compound 8a, wherein Ra, Rb, Rc and Rd are as previously defined, in a suitable polar organic solvent to obtain a corresponding bicyclic amine compound 9. Exemplary solvents for the reaction are selected from the group consisting of aqueous acetonitrile, DMF, aqueous DMF, and the like. One amino group of the diamine reagent can be optionally protected to differentiate the two diamine and deprotected prior to cyclization.
Cyclization of the bicyclic amine 9 by treatment with dilute acid in a suitable organic solvent affords the tricyclic derivatives of the invention. The reaction can be accomplished in a period of from about 1 to 10 days at temperatures from about room temperature to reflux. Exemplary acids are acetic acid or HCl. A suitable organic solvent is selected from alcoholic solvents, such as methanol, ethanol, propanol, and the like, or non polar solvent, such as benzene or toluene.
Optional deprotection of the compound obtained therefrom affords a tricyclic ketolide derivative of Formula (I), (III), and (V).
Carbonate-type derivatives of the invention are compounds represented by the general formula (II-A), (IV-A), and (VI-A), wherein A in the structural formula represents an oxygen heteroatom. A representative method for preparing carbonate compounds of the invention follows below in Scheme 7. 
(II-A), wherein R is xe2x80x94Mxe2x80x94R2 
(IV-A), wherein R is xe2x80x94C(O)xe2x80x94Mxe2x80x94R2 
(VI-A), wherein R is xe2x80x94SO2xe2x80x94Mxe2x80x94R2 
An intermediate 10 can be obtained by removing the cladinose group of compound 2 or 3. Oxidizing the 3-hydroxy of compound 10 provides compound 11. Compound 11 is converted to a cyclic carbonate compound of formula (II-A), (IV-A), and (VI-A), wherein A is xe2x80x94Oxe2x80x94, by reaction with carbonyldiimidazole and sodium hexamethyldisilazide or by reacting with triphosgene in pyridine. A summary of methods for the preparing the cyclic carbonate is described by Baker et al., J. Org. Chem., 1988, 53, 2340. The 2xe2x80x2-hydroxy of the cyclic carbonate can be optionally deprotected by methods as previously described.
Another method of preparing an 11,12-carbonate erythromycin derivative involves treatment of compound 1, preferably as the protected or deprotected oxime, with excess isocyanate reagent and optionally alkylating under the conditions as previously described for Scheme 1. The reaction provides an 11,12-carbonate derivative 13 having a 6-O-carbamate group optionally substituted on the nitrogen atom, as illustrated in Scheme 8 below. 
(II-A), wherein R is xe2x80x94Mxe2x80x94R2 
(IV-A), wherein R is xe2x80x94C(O)xe2x80x94Mxe2x80x94R2 
(VI-A), wherein R is xe2x80x94SO2xe2x80x94Mxe2x80x94R2 
Compound 13 provides a useful derivative from which the cladinose group can be optionally removed under hydrolysis conditions and the 3-hydroxy oxidized under reaction conditions as similar to those described for Scheme 4.
6-O-allyl- and 6-O-propargyl-substituted 11,12-diol, 11,12-carbamate, and tricyclic ketolide derivatives of erythromycin can be optionally coupled with an aromatic group to obtain compounds of formula I, II, II-A, III, IV, IV-A, V, VI, and VI-A, wherein R1 or R2 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, or Ar1xe2x80x94Ar2, wherein Ar1 and Ar2 are as previously defined.
A compound having 6-O-substitution 
can be coupled with a suitable aromatic group by methods of transition metal-catalyzed coupling. Methods for coupling aryl groups to the 6-O-allyl and 6-O-propargyl groups of macrolide derivatives are described in U.S. Pat. No. 5,866,549 and U.S. patent application Ser. No. 08/940,871, which are herein incorporated by reference.
A suitable aromatic group can be provided by an aromatic halide or aromatic trifluoromethanesulfonate reagent. Examples of such reagents include, but are not limited to, an aryl halide, substituted aryl halide, heteroaryl halide, or substituted heteroaryl halide, or a bifunctionalized aryl or heteroaryl precursor group.
Reaction of the allyl-substituted derivatives with an aryl halide is performed in the presence of Pd(II) or Pd(0) catalysts with promoters such as phosphines, arsines, amines, and inorganic bases in polar, aprotic solvents; see Organic Reactions, 1982, 27, 345-390. Preferably, the promoters are selected from triphenylphosphine, triphenylarsine, pyridine and triethylamine, potassium carbonate, and cesium fluoride. The aprotic solvents are as previously defined such as dimethylformamide, dimethyl sulfoxide, dimethylethane, acetonitrile, tetrahydrofuran, or mixtures thereof. The reaction is accomplished at temperatures from about room temperature to about 1 50xc2x0 C., depending on the reagents chosen and the nature of the aryl halide.
The 6-O-propargyl groups can be derivatized under Sonagashira conditions by combining the alkyne derivative with an aryl halide in the presence of a phosphine promoter and Cu(I) optionally in the presence of an organic base. Preferably, the organic base is triethylamine. Summary of the procedures, reagents, and solvents for coupling terminal alkynes with aryl halides is described in Tetrahedron Lett., 1975, 50, 4467-4470.
The propargyl carbamate derivatives can be derivatized with borane-THF in aprotic solvents at temperatures from about xe2x88x9220xc2x0 C. to about room temperature to provide vinyl boronic acid derivatives. The vinyl boronic acid derivatives can be reacted under Suzuki conditions with aryl halide reagents, catalysts and promoters to provide allyl products similar to the Heck coupling reaction of the aryl halide as described above. A thorough discussion of Suzuki conditions is provided in Chemical Reviews, 1995, Vol. 95, No. 7,2457-2483.
Representative compounds of the present invention were assayed in vitro for antibacterial activity as follows: Twelve petri dishes containing successive aqueous dilutions of the test compound mixed with 10 mL of sterilized Brain Heart Infusion (BHI) agar (Difco 0418-01-5) were prepared. Each plate was inoculated with 1:100 (or 1:10 for slow-growing strains, such as Micrococcus and Streptococcus) dilutions of up to 32 different microorganisms, using a Steers replicator block. The inoculated plates were incubated at 35-37xc2x0 C. for 20 to 24 hours. In addition, a control plate, using BHI agar containing no test compound, was prepared and incubated at the beginning and end of each test.
An additional plate containing a compound having known susceptibility patterns for the organisms being tested and belonging to the same antibiotic class as the test compound was also prepared and incubated as a further control, as well as to provide test-to-test comparability. Erythromycin A was used for this purpose.
After incubation, each plate was visually inspected. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of drug yielding no growth, a slight haze, or sparsely isolated colonies on the innoculum spot as compared to the growth control. The results of this assay, which relate to the antibacterial activity of the compounds of the invention, are reported below in Table 1.
In a separate assay representative compounds of the invention were assayed in vitro for antibacterial activity against H. Influenza Dill AMP R strain and S. Pneumonia, according to the protocol described above. The results of this assay, which relate to the antibacterial activity of compounds of the invention against the H. Influenza Dill AMP R and S. Pneumonia organisms, are shown below in Table 2.